Sequence Dependent Dynamics and Membrane Association of Intrinsically Disordered Proteins

Disordered Proteins (IDPs) challenge the conventional structure-function paradigm by exhibiting a lack of tertiary structure while performing a diverse array of functions. This dissertation sheds light on the intricate interplay between IDP sequences, dynamics, and their functional associations, advancing our comprehension of these biomolecules. A central inquiry in IDP research pertains to the encoding of function within their amino acid sequences. To elucidate the fundamental principles governing sequence-dependent dynamics, we conducted extensive molecular dynamics (MD) simulations on multiple IDPs. Our observations revealed that segments of residues demonstrating significant slow dynamics are concurrently stabilized by local inter-residue interactions or transient secondary structures. Membranes are an important class of binding partners for IDPs and upon membrane binding, IDPs can undergo structural transitions, ranging from a persistent disorder to the acquisition of partial structures. We first directed our simulations toward FtsQ and SepF, two proteins from Mycobacterium tuberculosis involved in the cell division apparatus and deciphered their interaction modes with acidic membranes and with FtsZ, a critical component of the Z-ring. WASP and N-WASP are homologous IDPs that necessitate binding to multiple regulators, to alleviate autoinhibition before catalyzing actin polymerization. Our simulations uncovered competitive binding between these regulators and revealed a mechanism to get away with the competition. Furthermore, we also explored competition between intra and inter molecular interactions in activation and that might relate to the activation. Finally, our free energy simulations delineated the pathways governing the synergistic activation process.